UC Irvine

Genetic data implicate microglia, the immune cells of the brain, in the development of Alzheimer’s disease (AD). Within the AD brain, microglia surround extracellular plaques and mount a chronic inflammatory response. These plaque-associated microglia (PAMs) are characterized by specific disease-associated gene expression signatures, including Apoe, Cst7, Trem2, Clec7a, Itgax, and Csf1. Data from animal models of AD have identified that microglia play critical roles in plaque formation and plaque compaction as well as contributing to synaptic and neuronal dysfunction and loss. However, examination of TREM2 knock-out mice, in which microglia fail to react to plaques, have produced data suggesting that the reaction of microglia to plaques is protective, counter to conventional views that microglia are a major factor in seeding plaques and contributing to neuronal cell death and synaptic loss via neuroinflammation, indicating that microglia may have both beneficial and dentrimental effects depending on model used or disease stage studied. A significant caveat with these experiments is that TREM2 is knocked out of all myeloid cells. Moreover, loss of TREM2 function in humans causes a neurodegenerative disease called Nasu-Hakola disease suggesting that the global knockout of TREM2 as utilized in the above studies induces neurodegeneration that may confound proper interpretations of its effects in AD. Thus, interpretations about the roles of microglia need to be reassessed with strategies that specifically delineate the contributions of PAMs from the non-plaque-associated microglia (NPAMs). We have developed novel strategies to target PAMs that can be used specifically during disease pathogenesis. Further, we include a genetic approach as well as a pharmacological approach to deliver specific therapeutic payloads to this cell population. My thesis further develops these tools and utilizes them to understand the roles of PAMs in AD pathogenesis.